Can Testosterone Induce Blood Clots and Thrombosis? Interview with Dr Charles Glueck

In my work collecting information for ExcelMale.com, I review abstracts daily on latest studies related to testosterone, men's health, nutrition, and more. I am always looking for studies that stand out and are no just repetitions of what we have seen before. Contrarian data to what I assume we know is what motivates me to read. In particular, I am looking for negative data and results in studies using testosterone. I have been using this hormone since 1993 to save my life and its quality and have not had any side effects. However, I know everyone is different and some people may have genetic or other variations that may make them susceptible to at least one side effect.

Good read:

What to do if you have a blood clot

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The first time I read a paper than mentioned thrombosis risk in people on testosterone replacement (read abstract at the end of this article), my goal is to get in contact with the author. Dr Charles Glueck was kind to reply for my request for an interview to help me educate physicians and patients. He is a graduate from Harvard and Western Reserve Universities and has over 35 years of medical practice and have produced over 600 publications. He is currently the Medical Director of the Jewish Hospital Cholesterol Center. To say that he has credentials is an understatement.

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I am impressed by his willingness to help anyone who may be concerned about this issue (he provides contact information below)

Here is the short interview:

Dr Glueck, Thank you so much for agreeing to educate my readers about your research.

Can you give give us a brief background of why you were interested in looking into thrombophilia and thrombosis in people on testosterone replacement therapy? Can you explain those terms to us?

Dr Glueck: As physicians who deal with deep venous thrombosis (DVT) and pulmonary embolus (PE), as well as blood clots in the eyes (central retinal vein and central retinal artery thrombosis), and ischemic stroke, and arterial blood clots, we realized that many of our referrals had started exogenous conventional testosterone therapy before sustaining their blood clots. Because we were very experienced with the diagnosis of thrombophilia and hypofibrinolysis, we hypothesized that the exogenous testosterone was interacting with underlying coagulation disorders producing the blood clots. We have now proven this in multiple publications.

In your best estimate or opinion, what is the incidence of this problem in men on testosterone replacement?

Dr Glueck: The incidence of DVT-PE or other clots in men on T therapy is not known, but our best estimates are that about 1-2% of men taking T will develop blood clots related to underlying inherited clotting abnormalities or to acquired thrombophilia (the antiphospholipid antibody syndrome). These men who landed in the hospital with dangerous and potentially lethal blood clots in the deep veins of the legs or in the lungs developed these clots within three months of starting testosterone therapy. None of them knew previously that they had an inherited clotting disorder that put them at greater risk for developing clots, nor did their providers test them before putting them on testosterone therapy.

You suggest that "thrombophilia should be ruled out before administration of exogeneous testosterone". How can that be done and are the tests commercially available or research tools? You used these tests in your study: factor V Leiden heterozygosity, high factors VIII and XI, high homocysteine, low antithrombin III, the lupus anticoagulant, high anticardiolipin antibody lgG, and the hypofibrinolytic 4G4G mutation of the PAI-l gene. Should all be performed? Would these tests be reimbursed by insurance and, if not, what do you think the retail value would be?

Dr Glueck: The 4 tests we would do include Factor V Leiden, Prothrombin gene, Factor VIII and Factor XI, all routinely available commercially at Lab Corp and Quest (big national labs), and at almost all regional labs as well. In our experience these tests are routinely covered by insurance. If not covered, I would estimate that the cost would be expensive, $800.

You also suggest a link between high estradiol with thrombophilia. Can you explain this finding? Would anastrozole or other E2 inhibitor improve outcome if used with TRT?


Dr Glueck: We have data to show that when T is aromatized in the body to estradiol (E2), the high E2 may be the agent which directly interacts with the underlying thrombophilia to produce the clots. We do not have enough data to know whether Arimidex used to lower E2 would be protective, but we know that Arimidex alone is prothrombotic in all of the thrombophilias and hence, probably not a good idea.

In your opinion, should all men on TRT be on low dose aspirin?

Dr Glueck: Low dose aspirin would have no effect on the clotting events seen in men on T who have underlying thrombophilia and I would not recommend it.

Are you planning to do any further studies on this troubling issue?

Dr. Gluek: We are working hard to better understand this troubling issue. If any of your readers have had DVT-PE or other clots while taking exogenous T, or during hCG or clomid therapy to raise T, we would be glad to help them out with expert consultative advice free of charge. Have them contact us by email ([email protected]) or by phone (513-924-8250) fax (513-924-8273) and we will advise them on what blood samples to have drawn, and how to deal with their problem. All of their information will, of course, be entirely private and totally confidential. We will also be glad to work with their doctors in their local communities.

Thank you so much for your time and I will be contacting you in a few months to see if you have any updated data for us.


____________________________________________

ClincAppl Thromb Hemost. 2014 Jan;20(1):22-30. Epub 2013 Apr 23.


Testosterone, thrombophilia, and thrombosis.

Glueck CJ, Richardson-Royer C, Schultz R, Burger T, Labitue F, Riaz MK, Padda J, Bowe D, Goldenberg N, Wang P.


Abstract

We describe thrombosis, deep venous thrombosis (DVT) pulmonary embolism (PE; n = 9) and hip-knee osteonecrosis (n = 5) that developed after testosterone therapy (median 11 months) in 14 previously healthy patients (13 men and 1 woman; 13 Caucasian and 1 African American), with no antecedent thrombosis and previously undiagnosed thrombophilia-hypofibrinolysis. Of the 14 patients, 3 were found to be factor V Leiden heterozygotes, 3 had high factor VIII, 3 had plasminogen activator inhibitor 1 4G4G homozygosity, 2 had high factor XI, 2 had high homocysteine, 1 had low antithrombin III, 1 had the lupus anticoagulant, 1 had high anticardiolipin antibody Immunoglobulin G, and 1 had no clotting abnormalities. In 4 men with thrombophilia, DVT-PE recurred when testosterone was continued despite therapeutic international normalized ratio on warfarin. In 60 men on testosterone, 20 (33%) had high estradiol (E2 >42.6 pg/mL). When exogenous testosterone is aromatized to E2, and E2-induced thrombophilia is superimposed on thrombophilia-hypofibrinolysis, thrombosis occurs. The DVT-PE and osteonecrosis after starting testosterone are associated with previously undiagnosed thrombophilia-hypofibrinolysis. Thrombophilia should be ruled out before administration of exogenous testosterone.

Click here for part 2:

Article: Second Interview with Dr Charles Glueck About Testosterone and DVT
 
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Latest study shows fewer DVT events in men on TRT vs not on TRT:

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Two blood tests are commonly used to measure a dog's ability to clot: prothrombin time, or PT, and activated partial thromboplastin time, or aPTT. These tests have an established normal reference range. Animals with results that are longer than normal are considered at risk of abnormal bleeding. However, when a clotting time was shorter than normal, clinicians have typically dismissed it.
"In the past," Silverstein said, "we've always said, no, it's probably that you pulled the sample incorrectly or the handling of the sample was inappropriate, even though logically you would think that a shorter time might indicate the animal is hypercoagulable.
"This study was attempting to say, can we actually use a shortened prothombin time or activated partial thromboplastin time to identify patients with hypercoagulability," she added.

http://m.phys.org/news/2016-05-animals-blood-clots.html
 
From a pharma company.


Association between Use of Exogenous Testosterone Therapy and Risk of Venous Thrombotic Events among Exogenous Testosterone Treated and Untreated Men with Hypogonadism.



Li H, et al. J Urol. 2016.
Authors
Li H1, Benoit K2, Wang W2, Motsko S2.
Author information
1Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana. Electronic address: [email protected].
2Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana.

Citation
J Urol. 2016 Apr;195(4 Pt 1):1065-72. doi: 10.1016/j.juro.2015.10.134. Epub 2015 Oct 31.

Abstract

PURPOSE: Limited information exists about whether exogenous testosterone therapy is associated with a risk of venous thrombotic events. We investigated via cohort and nested case-control analyses whether exogenous testosterone therapy is associated with the risk of venous thrombotic events in men with hypogonadism.

MATERIALS AND METHODS: Databases were reviewed to identify men prescribed exogenous testosterone therapy and/or men with a hypogonadism diagnosis. Propensity score 1:1 matching was used to select patients for cohort analysis. Cases (men with venous thrombotic events) were matched 1:4 with controls (men without venous thrombotic events) for the nested case-control analysis. Primary outcome was defined as incident idiopathic venous thrombotic events. Cox regression and conditional logistic regression were used to assess HRs and ORs, respectively. Sensitivity analyses were also performed.

RESULTS: A total of 102,650 exogenous testosterone treated and 102,650 untreated patients were included in cohort analysis after matching, and 2,785 cases and 11,119 controls were included in case-control analysis. Cohort analysis revealed a HR of 1.08 for all testosterone treated patients (95% CI 0.91, 1.27, p = 0.378). Case-control analysis resulted in an OR of 1.02 (95% CI 0.92, 1.13, p = 0.702) for current exogenous testosterone therapy exposure and an OR of 0.92 (95% CI 0.82, 1.03, p = 0.145) for past exogenous testosterone therapy exposure. These results remained nonstatistically significant after stratifying by exogenous testosterone therapy administration route and age category. Most sensitivity analyses yielded consistent results.

CONCLUSIONS: No significant association was found between exogenous testosterone therapy and incidents of idiopathic or overall venous thrombotic events in men with hypogonadism. However, some discrepant findings exist for the association between injectable formulations and the risk of overall venous thrombotic events.
 
Is that stratified by dose? My concern with these huge studies is whether the stats are being twisted by people getting tiny doses from gel/cream?
 
This thread is incredibly insightful and helpful. I've been having a very difficult time finding precise data on Clomid to increase T vs exogenous T for clotting risks. My partner just had a PE after 7+ years on either androgen or Clomid (last 4+ years). He spends a lot of time on airplanes and has some family history of clots. We're starting the difficult process of deciding how to proceed, though he'll definitely stay on anticoagulants for the next 6 months. I'm a little suspect that almost all of the studies on this topic are from one guy who I'd imagine is pretty anti HRT.
 
I'm currently a 49-year-old male who is been diagnosed with low testosterone , I currently take warfarin because I have factor five Leiden, have been dose stable for 8 years 7.5 mg ave per days 30 days, 5 mg daily with 1/2 of 5 mg every other day (pt/inr 2.4) this is tested at home and at dr office, I have been through 7 physicians and endocrinologists. All have remove me from their patient group because they feel issuing testosterone for treatment (255 (bottom 5 %) tested 6 days ago), is too risky stating lack of research on therapeutic warfarin patients. all of the research that I am able to find via the Internet and medical journals shows that testosterone therapy increases hypercoagulability with warfarin patients , which would indicate a lower level of warfarin needed should testosterone therapy be started to remain therapeutic , I have lived with this condition now for eight years I have a very good understanding of warfarin therapy along with my condition. I'm currently fighting an uphill battle to find a physician that is willing to treat the condition, thyroid has been tested and ruled out , tumor ruled out, enlarged prostate has been ruled out . Looking for help for a better quality of life not only for myself but my wife. Symptoms of low testosterone started showing up approximately six years ago they involved night sweats, lack of motivation , lack of sexual drive , muscle loss , slowed hair growth, Excessive weight gain (cortisol levels are at the high-end of the gray area) I also take lisinopril 20/12.5 for elevated blood pressure which started a year after warfarin therapy , A1 C levels also show elevated approximately one year after starting warfarin therapy, D3 deficiency also started one year after warfarin therapy.
 
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Geo1062

You may want to reach out to Defy Medical. If you are willing to sign a waiver they may be able to review your case.

The data shown in this long thread (this is page 5!) points to the fact that there is no consensus on the fact that men on warfarin with factor five Leiden may have increased risk of clotting or DVT issues on TRT.
 
I will be contacting Dr. Glueck with my concerns and report back in hopes I can ascertain some type of more aggressively-managed protocol for those of us at risk or who suspect risk while commencing TRT. Warfarin (coumadin) is only one type of anticoagulant, acting as a Vit K antagonist, blocking its action, and aspirin (and prescription anticoagulants like Plavix) only works to prevent platelet aggregation, however, there are other anticoagulants that work upon the clotting cascade entirely differently that as far as I know were not used in his research. These would be the older ones, i.e. Lovenox, heparin, and the much newer direct thrombin inhibitors like Xarelto, Eliquis and Pradaxa.

As far as AIs to control E2, I am at a loss as to what will not affect the clotting cascade in some way; they all do. Perhaps natural AIs are thew only safe ones. In my case, I have the opposite issue, as my E2 is almost non-existent. Yet another argument in favor of TRT.

Also – it would be interesting to see if having therapeutic phlebotomies would have prevented clots in those subject.



With the aggressive marketing of global TRT clinics, I expect we will see an incidence of thrombotic events increasing as more men commence TRT. This will greatly increase the necessity to overcome the hurdle as to what prophylactic measures can be taken to prevent future episodes, some of which can be fatal in the event a DVT causes PE.

The increased quality of life caused a strong addiction to TRT. I acquired substances at the gym. I had reoccurring PE's on xarelto, warfarin, and then lovenox. I was diagnosed with having antiphospholipid antibodies. Each PE occured almost immediately after starting weekly doses of Testosterone Enanthate (250mg). I realise now how foolish I was and I'm lucky to be alive. I made lifestyle changes that started with a healthier diet consuming more plant based foods and increased activity. I will never take any exogenous hormones again.

I am convinced that NOTHING will prevent DVT, if there are underlying conditions. It is not dose dependent either. I experimented, and each time produced the same result.
 
Hey, Marco, are you still around? I was wondering if you have any updates from the past few years.

Yes, still around. Nothing new. Still in limbo on this conundrum, but haven't given up looking into workarounds. At this point, I don't think there's anything currently available that doesn't have some degree of risk, so it's all about risk management, whether it's TRT, clomiphene, or something else.
 
The increased quality of life caused a strong addiction to TRT. I acquired substances at the gym. I had reoccurring PE's on xarelto, warfarin, and then lovenox. I was diagnosed with having antiphospholipid antibodies. Each PE occured almost immediately after starting weekly doses of Testosterone Enanthate (250mg). I realise now how foolish I was and I'm lucky to be alive. I made lifestyle changes that started with a healthier diet consuming more plant based foods and increased activity. I will never take any exogenous hormones again.

I am convinced that NOTHING will prevent DVT, if there are underlying conditions. It is not dose dependent either. I experimented, and each time produced the same result.

If you were using UGL gear, that's a whole other world of risks vs. medically-supervised TRT. Just curious - did you ever try Clomid as an alternative to exogenous testosterone?
 
Yes Clomid

If you were using UGL gear, that's a whole other world of risks vs. medically-supervised TRT. Just curious - did you ever try Clomid as an alternative to exogenous testosterone?
Agree, definitely bigger risks, but I didn't opt for low grade products. I was using Testosterone as a performance enhancer and to improve libido for several years. I had a very physical job, and Testosterone has many benefits not often outlined in the mainstream. As I aged, more-so as a libido boost. To answer your question, not as an alternative, but yes, Clomid was my choice medicine after a 3 month cycle. We called it Post Cycle Therapy. I usually did two cycles a year and took Clomid the following four weeks (tapered doses) of a cycle. Clots didn't form until roughly 15 years of use. Which is something I find very odd. I miss the feeling of well being, quick recovery from strain, and the strong libido. Definitely depressing and addictive.
 
Agree, definitely bigger risks, but I didn't opt for low grade products. I was using Testosterone as a performance enhancer and to improve libido for several years. I had a very physical job, and Testosterone has many benefits not often outlined in the mainstream. As I aged, more-so as a libido boost. To answer your question, not as an alternative, but yes, Clomid was my choice medicine after a 3 month cycle. We called it Post Cycle Therapy. I usually did two cycles a year and took Clomid the following four weeks (tapered doses) of a cycle. Clots didn't form until roughly 15 years of use. Which is something I find very odd. I miss the feeling of well being, quick recovery from strain, and the strong libido. Definitely depressing and addictive.

Yes, am familiar with Clomid being used for PCT, however, I was referring to it as a sole TRT alternative as the whole reason anyone would want to use it for that which is two-pronged - 1) to avoid testicular atrophy and azoospermia that is associated with frank TRT, and 2) less or zero incidence of HPTA suppression that is also a given with TRT.
 
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its a known fact that testosterone will increase RBC, but there is a simple fix for this as you all know, donate! however I agree that this side needs to be added to the label as many doctors today have no clue how to treat it, some even refuse to give a script for blood letting. so I agree with FDA on adding this side effect to the label.

True, but donating blood can tank ferritin levels (which is aggro, esp as it can affect the thyroid).

Saw this thread on Google re blood clots (I am experiencing pains that are associated with clots, so will get it check out first thing).
 
good to know, so not sure, but hoping my recent left calf dvt was caused by hereditary high cholesterol along with lack of exercise and cutting off circulation due to my occupation....
 

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